C-223/01

OPINION OF MR JACOBS — CASE C-223/01

O P I N I O N OF ADVOCATE GENERAL JACOBS delivered on 23 January 2003 1

1. In this case the Østre Landret (Eastern for a generic version of that product may in Regional Court), Denmark, has referred certain circumstances be made on the basis two questions on the interpretation of of a procedure which is simpler than the C o u n c i l D i r e c t i v e 6 5 / 6 5 / E E C of procedure for obtaining the initial market- 26 January 1965 on the approximation of ing authorisation. provisions laid down by law, regulation or administrative action relating to medicinal products. 2

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The relevant EC legislation sation and supervision of medicinal prod- " ucts for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products. 5

4. The preamble to Directive 65/65 states: 6. Under Article 4 of Directive 65/65, the person responsible for placing a medicinal product on the market is to make appli- cation to the competent authority of the Member State concerned. The application is to be accompanied by a number of '... the primary purpose of any rules con- prescribed particulars and documents, cerning the production and distribution of including, under point 8 of the third para- medicinal products must be to safeguard graph of Article 4, results of physico- public health; chemical, biological or microbiological tests, pharmacological and toxicological tests and clinical trials.

... however, this objective must be attained 7. Point 8(a), however, provides for an by means which will not hinder the deve- abridged application or simplified pro- lopment of the pharmaceutical industry or cedure to be available by way of exception trade in medicinal products within the in certain circumstances. In so far as Community...'. 4 relevant, point 8(a) provides as follows:

'The applicant shall not be required to 5. Under Article 3 of Directive 65/65, no provide the results of pharmacological and medicinal product may be placed on the toxicological tests or the results of clinical market of a Member State unless a market- trials if he can demonstrate: ing authorisation has been issued by the competent authorities of that Member State or an authorisation has been granted in accordance with Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authori-

Authorisation shall likewise be refused if the particulars and documents submitted in support of the application do not comply with Article 4.'

11. Article 9a of Directive 65/65 provides as follows: ... there are reasons of public policy for not conducting repetitive tests on humans or animals without over-riding cause'. 7

6 — Cited in note 2. 'After an authorisation has been issued, the 7 — Second and fourth recitals. person responsible for placing the product I-11814

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on the market must, in respect of the 14. Article 1 of Directive 75/318 9 pro- methods of preparation and control pro- vides: vided for in points 4 and 7 of the [third] paragraph of Article 4, take account of technical and scientific progress and intro- duce any changes that may be required to enable that medicinal product to be manu- factured and checked by means of generally 'Member States shall take all appropriate accepted scientific methods....' 8 measures to ensure that the particulars and documents which must accompany appli- cations for authorisation to place a medici- nal product on the market (marketing authorisation), pursuant to point... 8 of Article 4, [third] paragraph, of Directive 65/65/EEC, are submitted by the persons concerned in accordance with the Annex to 12. The first paragraph of Article 11 of this Directive. Directive 65/65 provides:

...'

Such information shall be collated with data on consumption of medicinal prod- (a) must verify whether the particulars ucts. submitted in support of the application comply with the said Article 4 and examine whether the conditions for issuing an authorisation to place medicinal products on the market (marketing authorisation) are complied This system shall also collate information with;... on frequently observed misuse and serious abuse of medicinal products.

Article 29b

Article 29a

For the purpose of this Directive, the In order to ensure the adoption of appro- following definitions shall apply: priate regulatory decisions concerning the

11 — Second Council Directive of 20 May 1975 on the approximation or provisions laid down by law, regu- lation or administrative action relating to medicinal products, OJ 1975 L 147, p. 13, as amended in particular by Directives 89/341 and 93/39, both cited in note 2. — "adverse reaction" means a reaction Articles 29a to 29h of Directive 75/319 have been amended with effect from 30 June 2000 by Commission which is harmful and unintended and Directive 2000/38/EC of 5 June 2000, OJ 2000 L 139, which occurs at doses normally used in p. 28, which further strengthens the phamaracovigilance obligations imposed. man for the prophylaxis, diagnosis or

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The person responsible for placing the medicinal product on the market shall have permanently and continuously at his dis- 1.The person responsible for placing the posal an appropriately qualified person medicinal product on the market shall be responsible for pharmacovigilance. required to record and to report all sus-

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pected serious adverse reactions which are The Member States may impose specific brought to his attention by a health care requirements on medical practitioners, in professional to the competent authorities respect of the reporting of suspected serious immediately, and in any case within 15 or unexpected adverse reactions, in par- days of their receipt at the latest. ticular where such reporting is a condition of the authorisation.

2. In addition, the person responsible for placing the medicinal product on the mar- ket shall be required to maintain detailed records of all other suspected adverse Article 29f reactions which are reported to him by a health care professional.

The Member States shall ensure that Unless other requirements have been laid reports of suspected serious adverse reac- down as a condition of the granting of tions are immediately brought to the atten- authorisation, these records shall be sub- tion of the [European Agency for the mitted to the competent authorities Evaluation of Medicinal Products] and the immediately upon request or at least every person responsible for placing the medici- six months during the first two years nal product on the market, and in any case following authorisation, and once a year within 15 days of their notification, at the for the following three years. Thereafter, latest. the records shall be submitted at five-yearly intervals together with the application for renewal of the authorisation, or immedi- ately upon request. These records shall be accompanied by a scientific evaluation.

Where as a result of the evaluation of adverse reaction reports a Member State The facts and the questions referred considers that a marketing authorisation should be varied, suspended or withdrawn, it shall forthwith inform the Agency and the person responsible for placing the medicinal product on the market.

17. The present case concerns the medici- nal product Losec. Losec, reportedly the world's largest-selling pharmaceutical, is used to treat and prevent peptic ulcers and In case of urgency, the Member State reflux oesophagitis (heartburn). It contains concerned may suspend the marketing of omeprazole, a substance called a proton- a medicinal product, provided the Agency pump inhibitor which works by blocking a is informed at the latest on the following particular mechanism in the stomach called working day. the proton pump which controls acid production, thereby reducing the amount of stomach acid produced.

18. Losec Enterokapsler (Losec entero-cap- sules; 'Losec capsules') were developed by Article 33 the Astra group and have been approved and marketed in Denmark since 1989. On 3 February 1997 AstraZeneca A/S, a Dan- ish company in the Astra group, applied to the Lægemiddelstyrelse (the Danish com- petent authority for the purpose of Direc- tive 65/65) for approval for Losec Enter-

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otabletter (Losec entero-tablets; 'Losec tab- ingredient (magnesium salt of omeprazole lets'). The Lægemiddelstyrelse issued a acid as opposed to omeprazole acid). It marketing authorisation for Losec tablets should be noted that the question whether on 22 September 1997. Losec capsules are 'essentially similar' to Losec tablets within the meaning of point 8(a)(iii) is not at issue in the present case, which concerns solely the interpre- tation of the marketing condition in that provision.

20. AstraZeneca has explained before the national courts that Losec capsules con- 22. The Lægemiddelstyrelse approved and tinue to be approved and marketed in issued marketing authorisation for Ome- Austria, France, Greece, Ireland, Italy, prazol Generics Entero-capsules on Luxembourg, Portugal, and the United 30 November 1998. Kingdom. In some of those Member States, Losec capsules are marketed alongside Losec tablets. It appears to be accepted that Losec tablets and Losec capsules are what are known as therapeutic equivalents - that is to say, they contain the same active ingredient (omeprazole) - and are bioequi- valent in that that ingredient is absorbed by 23. AstraZeneca sought judicial review of the body at the same rate and to the same the Lægemiddelstyrelse's decision of extent when taken orally. It appears that, in 30 November 1998 before the Østre Land- addition to their different presentation, the sret, arguing in particular that point 8(a)(iii) products differ in the form of the active requires that there must be a valid market-

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25. Generics UK Ltd intervened in support of the Lægemiddelstyrelse. 29. The Østre Landsret notes in conclusion that although in Generics 12 the Court of Justice ruled on the substantive conditions in point 8(a)(iii) governing whether a medicinal product 'is essentially similar to' the reference product, the Court has 26. The Østre Landsret considers that the not yet ruled on the provision's conditions Danish version of point 8(a)(iii) is not as to time. It has accordingly referred the wholly clear on this point: there is disagree- following questions to the Court for a ment as to whether the auxiliary verb 'har preliminary ruling: været' (has been) relates simply to the condition that the reference product has been approved in the Community or relate also to the condition of being marketed in the Member State for which the application is made. ' 1 . In a case where an undertaking applies for marketing authorisation on the basis of an abridged application (sim- plified procedure) under Article 4, third paragraph, point 8(a)(iii) of the first 27. The Østre Landsret adds that there is medicinal products directive (Council moreover disagreement between the parties on the interpretation of the term 'marketed' in point 8(a)(iii). 12 — Case C-368/96 [1998] ECR I-7967.

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Directive 65/65/EEC as subsequently there be approval in the form of amended) and states that the product marketing authorisation for the refer- for which marketing authorisation is ence product in the Member State for sought is essentially similar to a refer- which the application is made?' ence product which has been approved in the Community for the necessary period of time pursuant to the direc- tive, is it necessary and sufficient that the reference product:

35. The Danish and Norwegian Govern- Observations of the parties ments and the Commission consider that the reference product must still be mar- keted in the Member State for which the application is made at the time of the application.

32. Written observations have been sub- mitted by AstraZeneca, Generics (inter- vener before the national court), the Danish Government both in its capacity as a Member State and on behalf of the Læge- middelstyrelsen, the Netherlands and Nor- 36. AstraZeneca supports its view prin- wegian Governments, the Commission and cipally by reference to public health con- the EFTA surveillance authority, all of cerns. It notes that once a marketing auth- which with the exception of the Nether- orisation has been granted for the generic lands Government were represented at the product, the holder of that authorisation is hearing. obliged to monitor use of the product and provide up-to-date information with regard to pharmacovigilance and other data which are important for assessing the safety and efficacy of the product. Until the auth- orisation for the generic product is granted, the competent authority in the Member 33. AstraZeneca considers that, in order State where the application for that auth- for a marketing authorisation to be valid in orisation is made - which is required to accordance with point 8(a)(iii), the refer- assess whether the quality, safety and ence product must be marketed both when efficacy criteria are satisfied when the the application is made and when the authorisation is granted - will have to rely authorisation is granted. on the existence of an authorisation for the reference product and the resulting obli- gations on its holder. When the authori- sation for the reference product is with- drawn, all those pharmacovigilance obli- gations disappear and the competent auth- 34. Generics, the Netherlands Government ority cannot therefore count on the and the EFTA Surveillance Authority con- particulars and documents available to it sider that it is sufficient that the reference being complete and up-to-date. Although it

38. Those parties submit further that if it were a condition for the grant of a generic authorisation that the reference product be marketed when the application for that 37. Generics, the Netherlands Government authorisation was filed, the manufacturer and the EFTA Surveillance Authority seek of the reference product could effectively to counter those arguments by reference in bar generic manufacturers from using the particular to the pharmacovigilance abridged procedure and thereby render requirements imposed by Directive point 8(a)(iii) redundant. That would run 75/319 14 which subsist even after with- counter to the aims of point 8(a)(iii) as set drawal of the original authorisation. The out in the preamble to Directive 87/21 15 Netherlands Government submits that which include the reduction of animal and when there is no authorisation for a given human testing (required to support an medicinal product, that product cannot be application under the full procedure). The sold and there can therefore be no new Netherlands Government adds that it is information on side-effects and adverse also apparent from the preamble to Direc- reactions. It notes that in any event it is tive 87/21 that point 8(a)(iii) seeks to not only the holder of an authorisation who stipulate precisely the cases in which the is bound to report suspected adverse reac- abridged procedure may be used. Differ- tions to the competent authorities since ences in the way in which the abridged Article 29e of Directive 75/319 requires the procedure is applied in the different Member States to take all appropriate Member States must therefore be pre- measures to encourage doctors and other vented. If the provision is interpreted so health care professionals to make such that a generic product may be marketed in

40. The Danish Government and the Com- mission submit that the wording of 39. The Norwegian Government and the point 8(a)(iii) in the English, French and Commission also take the view that, where German versions is clear. The Commission the marketing authorisation for the refer- adds that Article 4 of Directive 65/65 ence product is withdrawn before the concerns solely the conditions of applying generic authorisation is issued but the for a marketing authorisation and accord- reference product is still marketed in other ingly does not concern the issue of that Member States, the competent authority of authorisation. Since the time the appli- the Member State where application is cation is made is decisive for determining made can satisfy its pharmacovigilance whether the conditions of issue of the duties by virtue of the exchange of infor- authorisation for a generic product are mation provided for by Directive 75/319; satisfied, the marketing authorisation for moreover that authority will still have the the reference product must be in force file for the original full application. The when that application is made. The Danish Danish Government however does not and Norwegian Governments also consider consider it relevant whether the reference that the interpretation advocated by Astra- product is still marketed in other Member Zeneca would enable the holder of a States, noting that Directive 65/65 16 - in marketing authorisation to block generic contrast to Regulation No 2309/93 17 copies by withdrawing that authorisation. which provides for a central marketing authorisation - set up a system under which the authorities of each Member State issue authorisations for medicinal products mar- keted in that State. The Danish Govern- ment considers that public health is none Assessment the less safeguarded since all the necessary information concerning the reference prod- uct is available to the competent authority of the Member State in which application for the generic authorisation is made, that 41. The text of the relevant phrase in product having been authorised on the point 8(a)(iii) reads as follows: basis of a complete application. The national authorities can thus control what

43. That interpretation follows unequivo- Generics, focusing in particular on the cally from the English version. It is also English version, describes that wording as supported, as the Danish Government and 'at best unclear and at worst ambiguous as the Commission submit, by the French and to the marketing requirements in the German versions: on a natural reading the Member State concerned'. After an exhaus- temporal condition there spelt out 1 9 could tive analysis of the objectives and legislative not be satisfied by showing that the refer- history of Directive 87/21, 18 which intro- ence product had been marketed at some duced the provision, Generics concludes time before the application for the generic that point 8(a)(iii) should be interpreted as authorisation was made but was no longer requiring that the reference product must marketed when that application was made. have been at least some time previously It may be noted that the EFTA Surveillance authorised prior to the filing of the generic Authority concedes that a literal interpre- application in the Member State concerned. tation of point 8(a)(iii) entails that con- That view is shared by the Netherlands clusion. Government and the EFTA Surveillance Authority.

45. Nor do I accept the interpretation Member State for which the application is advocated by AstraZeneca, namely that, made will be unable to discharge its duties in order for a marketing authorisation to be of pharmacovigilance. That argument valid in accordance with point 8(a)(iii), the appears to be based in particular on two reference product must be covered by a provisions of the legislation. Before turning marketing authorisation both when the to the substance of AstraZeneca's concerns, application is made and when the auth- I will look at the text of those provisions. orisation is granted. To my mind the scheme of the provision precludes such an interpretation. As the Commission points out, Article 4 of Directive 65/65 is con- cerned with the procedure for applications for abridged authorisations. The first para- graph provides that, in order to obtain an authorisation to place a medicinal product 47. First, AstraZeneca refers to Article 4(a) on the market, the person responsible for of Directive 75/319, 2 0 which requires the placing that product on the market is to competent authorities of the Member States make application to the competent auth- to 'examine whether the conditions for ority of the Member State concerned. The issuing an authorisation to place medicinal third paragraph requires the application to products on the market... are complied be accompanied by specified particulars with'. AstraZeneca maintains that that and documents. Those particulars and provision requires the competent auth- documents clearly speak from the time the orities to verify whether the criteria of application is made. They include, under quality, safety and efficacy are satisfied point 8 of the third paragraph of Article 4, when the authorisation is issued. results of physico-chemical, biological or microbiological tests, pharmacological and toxicological tests and clinical trials. Point 8(a)(iii) states that the applicant 'shall not be required to provide the results of [those tests and trials] if he can demonstrate... that the medicinal product is essentially similar to a product which... is marketed in the 48. I am not convinced that as a matter of Member State for which the application is construction Article 4(a) bears that mean- made'. I can see nothing in the scheme or ing. The full text is as follows: wording of the provision to support the view that that requirement to demonstrate that the reference product is marketed continues until the generic authorisation is granted.

51. However, it is clear that the primary 49. Second, AstraZeneca bases its argu- purpose of the Community legislation on ment on Article 5 of Directive 65/65 21 the marketing of medicinal products is to which lists the circumstances in which a safeguard public health. 22 The substance of competent authority is to refuse to issue a AstraZeneca's argument is that its inter- marketing authorisation. The first para- pretation must prevail if public health is graph of that article requires authorisation not to be prejudiced, and in particular that, to be refused if 'after verification of the when the authorisation for the reference particulars and documents listed in Article 4 product is withdrawn, the competent auth- it proves that the medicinal product is ority is not in a position to ensure that it is harmful in the normal conditions of use, or in possession of up-to-date information on that its therapeutic efficacy is lacking or is the quality, safety and efficacy of the insufficiently substantiated by the appli- reference product when it grants the gen- cant, or that its qualitative and quantitative eric authorisation composition is not as declared'. Astra- Zeneca submits that the competent auth- ority will be unable to assess whether the quality, safety and efficacy criteria are satisfied when the authorisation is granted unless the reference product continues to be marketed up to that point. 52. I do not accept that argument.

22 — See the first recital in the preamble to Directive 65/65, set 21 — Set out in paragraph 10 above. out in paragraph 4 above.

53. First, the person responsible for placing professionals to report suspected adverse the product on the market is required by reactions to the competent authorities 25 Article 29c of Directive 75/319 2 3 to pro- and to ensure that reports of suspected vide for the collection and collation at a serious adverse reactions are immediately single point within the Community of brought to the attention of the Agency and information about all suspected adverse the person responsible for placing the reactions reported to it and to ensure that medicinal product on the market. 26 any request from the competent authorities for the provision of additional information necessary for the evaluation of the benefits and risks of the product is answered fully and promptly. Thus the competent auth- ority of the Member State where an appli- cation under the abridged procedure is 56. AstraZeneca itself stresses the rigour of made may, if it considers it appropriate, those requirements in its written observa- approach the company which holds the tions in support of its argument that up- marketing authorisation for the reference to-date information will not be available to product in another Member State before the competent authority of the Member issuing an authorisation for the generic State where application for a generic auth- product. orisation is made once the marketing auth- orisation for the reference product has been withdrawn. The abovementioned phar- macovigilance obligations will however continue to apply for so long as the reference products have marketing auth- 54. Second, Article 29d of Directive orisations in other Member States. 75/319 24 requires the person responsible for placing the product on the market to record and promptly report to the compet- ent authorities all suspected serious adverse reactions brought to his attention by a health care professional and to maintain detailed records of all other suspected 57. An analogy may be drawn with the adverse reactions so reported. Those rec- situation of a parallel importer where the ords are to be submitted to the competent marketing authorisation for the reference authorities at periodic intervals but at any product is withdrawn for reasons uncon- event 'immediately on request'. nected with the safety of the product. Although it is clear from the case-law of the Court that the parallel import of medicinal products is not governed by Directive 65/65, 2 7 the question whether in such circumstances adequate phar- 55. It may be noted that the Member States are to take all appropriate measures to encourage doctors and other health care 25 — Article 29e of Directive 75/319, set out in paragraph 16 above. 26 — Article 29f of Directive 75/319, set out in paragraph 16 above. 27 — See the case-law summarised in Case C-172/00 Ferring 23 — Set out in paragraph 16 above. Arzneimittel, judgment delivered on 10 September 2002, 24 — Set out in paragraph 16 above. at patagraphs 19 to 22.

61. Of course if the marketing authori- sation for the reference product is with- drawn on grounds of public health, it 59. Admittedly, as AstraZeneca states, the would clearly be inappropriate for a gen- abovementioned pharmacovigilance obli- eric authorisation to be issued after with- gations will subsist only as long as the drawal of the earlier authorisation. How- reference product continues to be marketed ever, since - as AstraZeneca points out in its written observations - Article 33(2) of Directive 75/319 requires the person 28 — Cited in note 27, paragraphs 36 and 38 of the judgment, responsible for the marketing of a medici- citing Case C-94/98 Rhône-Poulenc Rorer and May & Baker [1999] ECR I-8789, paragraph 46. nal product immediately to notify the

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64. It is also the interpretation agreed on by the European Medicines Agencies Co- operation on Legal and Legislative Issues (Emacolex), which consists of officials 63. That interpretation is also consistent working on legal issues in the Member with the understanding of the provision on which the Commission has based its pub- 30 — Cited in note 5. 31 — November 2002. 29 — Set out in paragraph 8 above. 32 — Paragraph 4.2.4 of chapter 1, emphasis in original.

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States, the European Commission and the the Court's decision in Generics 35 will Agency. 33 often mean that reference can be made to the newer version, even if its authorisation was obtained within the 6 or 10 year period of data protection. As I argue in my Opinion delivered today in Novartis, 36 such reference may be made whenever a variant product differs from its original as regards its pharmaceutical form, dose or 65. Although neither the Commission's therapeutic use. guidelines 34 nor the view of Emacolex is binding, it is none the less in my view significant that both those bodies, which are active in the field of pharmaceutical regulation, have arrived at the same inter- pretation. The second question

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69. I agree with that view. 72. Third, as AstraZeneca, the Danish and Netherlands Governments and the Com- mission submit, that interpretation is con- sistent with the Commission's 'Notice to Applicants', which states: '"Marketing" must be understood as "authorised" as the medicinal product has been authorised under a "marketing authorisation".'

37 — See the first recital in the preamble, set out in paragraph 4 above. 39 — Set out in paragraph 16 above. 38 — See paragraphs 14 and 15 above. 40 — Set out in paragraph 12 above.

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Conclusion

74. I am accordingly of the opinion that the questions referred by the Østre Landsret should be answered as follows:

In order to benefit from the abridged procedure provided by point 8(a)(iii) of the third paragraph of Article 4 of Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by law, regulation or adminis- trative action relating to medicinal products, an applicant for a marketing authorisation must demonstrate that at the time of the application the reference product has a valid marketing authorisation in the Member State for which the application is made.